Salts and solid forms of Sonrotoclax intermediates

Abstract

Disclosed herein are salts and solid forms of Sonrotoclax intermediates and methods for their preparation.

Description

Technical Field

[0001] Disclosed herein are salts and solid forms of Sonrotoclax intermediates and methods for making Sonrotoclax. Background Art

[0002] International publication WO 2019 / 210828 discloses a series of Bcl-2 inhibitors, particularly 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (hereinafter referred to as Sonrotoclax).

[0003] The method for making Sonrotoclax disclosed therein is not ideal for scale-up because the intermediate methyl 4-(2-{(2S)-2-[2-(propan-2-yl)phenyl]pyrrolidin-1-yl}-7-azaspiro[3.5]nonan-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoate (Compound 2) is obtained as an oil or liquid at low chemical purity. Therefore, a new method for making Sonrotoclax is desired. Summary of the invention

[0004] Provided herein are salts of Compound 2 and crystalline and amorphous forms thereof. Further provided herein are methods of making salts of Compound 2 and crystalline and amorphous forms thereof. Further provided herein are methods of making Sonrotoclax using salts of Compound 2 and crystalline and amorphous forms thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Figure 1A The XRPD pattern of the Form A oxalate salt is shown.

[0006] Figure 1B The TGA / DSC curve of Form A oxalate is shown.

[0007] Figure 1C The NMR spectrum of the oxalate form A is shown.

[0008] Figure 2A The XRPD pattern of Form B oxalate is shown.

[0009] Figure 2B The TGA / DSC curve of Form B oxalate is shown.

[0010] Figure 2C The NMR spectrum of the Form B oxalate salt is shown.

[0011] Figure 3A The XRPD pattern of Form C oxalate is shown.

[0012] Figure 3B The TGA / DSC curve of Form C oxalate is shown.

[0013] Figure 3C The NMR spectrum of the oxalate Form C is shown.

[0014] Figure 4A The XRPD pattern of the D-oxalate salt is shown.

[0015] Figure 4B The TGA / DSC curve of the D-oxalate salt is shown.

[0016] Figure 4C The NMR spectrum of the D-oxalate salt is shown. DETAILED DESCRIPTION

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0018] As used herein, the term "solvate" refers to a crystalline form of Compound 2 containing a solvent.

[0019] As used herein, the term "crystal form" or "crystalline form" refers to a crystalline solid form. In certain embodiments, the crystalline form of a substance may be substantially free of amorphous forms and / or other crystalline forms. In certain embodiments, the crystalline form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% (by weight) of one or more amorphous forms and / or other crystalline forms. In certain embodiments, the crystalline form of a substance may be physically and / or chemically pure. In certain embodiments, a crystalline form of a substance can be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and / or chemically pure.

[0020] As used herein, and unless otherwise specified, the term "amorphous" or "amorphous form" means that the substance, component or product in question is substantially not crystalline as determined by X-ray diffraction. In particular, the term "amorphous form" describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In certain embodiments, the amorphous form of a substance may be substantially free of other amorphous forms and / or crystalline forms. In certain embodiments, the amorphous form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45% or less than about 50% (by weight) of one or more other amorphous forms and / or crystalline forms. In certain embodiments, the amorphous form of a substance may be physically and / or chemically pure. In certain embodiments, the amorphous form of a substance is about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and / or chemically pure.

[0021] As used herein, the term "about" when used for XRPD peak positions refers to the inherent variability of the peaks, which depends on the calibration of the instrument, the method used to prepare the crystalline form of the present disclosure, the age of the crystalline form, and the type of instrument used in the analysis. The variability of the instrument used for XRPD analysis is about ± 0.2 ° 2θ.

[0022] As used herein, the term "about" when applied to the onset of a DSC endothermic peak refers to the inherent variability of the peak, which depends on the calibration of the instrument, the method used to prepare the samples of the present disclosure, and the type of instrument used in the analysis. The variability of the instrument used for DSC analysis is about ±1°C.

[0023] Unless otherwise indicated, the term "about" as used herein, in addition to the previous definition, means that a number (eg, temperature, pH, volume, etc.) may vary within ±10%, preferably within ±5%.

[0024] An experimental measurement, result, or observation, such as an XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermal curve is said to be "substantially consistent" with another XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermal curve when one skilled in the art considers them to represent the same single crystalline form of the same compound. Thus, an XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermal curve that is substantially consistent with one or more of the patterns provided herein may be identical, or, more likely, may be slightly different. For example, an XRPD pattern that is slightly different from one or more of these patterns may not necessarily show every one of the lines of the diffraction pattern presented herein and / or may show slight changes in the appearance or intensity of these lines or shifts in the positions of these lines. These differences are typically due to differences in the conditions involved in acquiring the data or differences in the purity of the samples used to acquire the data. One skilled in the art will be able to determine whether a sample of a crystalline compound is in the same form as or a different form from the forms disclosed herein by comparing its XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermal curve to a corresponding XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermal curve disclosed herein.

[0025] Unexpectedly, the salt of compound 2 (preferably the oxalate of compound 2, even more preferably the crystal of the oxalate of compound 2) is a solid with very low viscosity and very good stability. The crystalline form of the oxalate of compound 2, especially the form B of the oxalate, can be obtained with very good purity without further purification, which is suitable for large-scale industrial processes. The particle size of form B is 1-50 μm, preferably 1-30 μm, more preferably 5-20 μm, even more preferably 5-10 μm. Such a particle size can be easily and quickly obtained by filtration.

[0026] Aspect 1. A salt having formula (I): wherein [acid] is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentisic acid, nicotinic acid, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; n is from about 0.5 to about 3, Preferably, n is 0.5 to 2; more preferably, n is 0.5 to 1.5; even more preferably, n is 1. In certain embodiments, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1 or 3.0.

[0027] Aspect 2. The salt according to aspect 1, wherein [acid] is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and / or nitric acid.

[0028] Aspect 3. The salt as described in Aspect 1, wherein [acid] is selected from tartaric acid (L-tartaric acid or D-tartaric acid), malic acid, citric acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; preferably, [acid] is selected from oxalic acid.

[0029] Aspect 4. The salt according to aspect 1, which is an oxalate having formula (II): wherein n is from about 0.5 to about 3; Preferably, n is 0.5 to 2; more preferably, n is 0.5 to 1.5; even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0; even more preferably, n is 1.0 Even more preferably, the salt is an oxalate salt having formula (III):

[0030] Aspect 5. A crystalline form of a compound having formula IV wherein [acid] is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentisic acid, nicotinic acid, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; [Solvent] is selected from H2O or an organic solvent; n is a number from about 0.5 to about 3; m is a number from about 0.0 to about 5.0.

[0031] Aspect 6. The crystalline form of Aspect 5, wherein [acid] is selected from the group consisting of: an inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and / or nitric acid; or an organic acid selected from fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentisic acid, nicotinic acid, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; Preferably, [acid] is selected from tartaric acid (L-tartaric acid or D-tartaric acid), malic acid, citric acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; More preferably, [the acid] is selected from oxalic acid.

[0032] Aspect 7. The crystalline form of any one of Aspects 5-6, wherein n is from about 0.5 to about 3; Preferably, n is from 0.5 to 2; more preferably, n is from 0.5 to 1.5; even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0; even more preferably, n is 1.0.

[0033] Aspect 8. A crystalline form as described in any of Aspects 5-7, wherein the [solvent] is selected from MeOH, EtOH, i-PrOH, n-PrOH, n-BuOH, t-BuOH, DCM, CPME, toluene, acetone, butanone, pentanone, H2O, MeCN, THF, diethyl ether, propyl ether, n-heptane, hexane, 1,4-dioxane or EtOAc.

[0034] Aspect 9. The crystalline form of any one of Aspects 5-8, wherein m is a number from about 0.0 to about 3.0, preferably from about 0.0 to about 2.0, more preferably, m is a number selected from the group consisting of 0.1±0.1, 0.5±0.1, 1.0±0.2, 1.5±0.2 and 2.0±0.2, even more preferably, m is 0 to 0.2, 0.95 to 1.05, 1.05 to More preferably, m is 0.98 to 1.02, 1.08 to 1.12 or 1.48 to 1.52, 1.95 to 2.15; even more preferably, m is 0, 0.1, 0.2, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 or 7.0.

[0035] Aspect 10. A crystalline form of an oxalate salt of Compound 2, which is (a) Crystalline Form A characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2θ angle values ​​independently selected from the group consisting of: 3.89±0.2, 7.69±0.2, 10.55±0.2, 10.84±0.2, 11.21±0.2, 11.68±0.2, 12.31±0.2, 13.02±0.2, 13.83±0.2, 14.69±0.2, 15.36±0.2, 15.58±0.2, 16.60±0.2, 17.58±0.2, 18.39±0.2, 18.98±0.2, 19.32±0.2, 19.81±0.2, 20.37±0.2 , 21.05±0.2, 21.61±0.2, 21.91±0.2, 22.49±0.2, 23.09±0.2, 23.48±0.2, 24.15±0.2, 24.76±0.2, 25.44±0.2, 25.66±0.2, 26.18±0.2, 26.67±0.2, 27.00±0.2, 28.11 ±0.2, 28.71±0.2, 29.09±0.2, 29.55±0.2, 29.91±0.2, 31.52±0.2, 32.18±0.2, 32.80±0.2, 34.49±0.2, 34.97±0.2, 36.66±0.2, 38.52±0.2, 39.32±0.2, and 39.71±0.2; or (b) crystalline Form B characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2θ angle values ​​independently selected from the group consisting of: 4.05±0.2, 8.00±0.2, 10.79±0.2, 11.23±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 12.95±0.2, 13.92±0.2, 15.55±0.2, 16.03±0.2, 16.83±0.2, 17.14±0.2, 17.76±0.2, 18.41±0.2, 19.38±0.2, 20.08±0.2, 20.50±0.2, 21.04±0.2, 21.66±0.2, 22.08±0.2, 22.52±0.2, 23.34±0.2, 23.72±0.2, 24.09±0.2, 24.82±0.2, 25.31±0.2, 25.66±0.2, 26.02±0.2, 27.21± 0.2, 27.78±0.2, 28.21±0.2, 28.53±0.2, 29.01±0.2, 31.06±0.2, 31.45±0.2, 32.28±0.2, 33.02±0.2, 34.67±0.2, 35.30±0.2, 36.02±0.2, and 38.00±0.2; or (c) crystalline Form C, characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2θ angle values ​​independently selected from the group consisting of: 3.80±0.2, 4.01±0.2, 8.00±0.2, 10.42±0.2, 11.31±0.2, 11.55±0.2, 12.02±0.2, .2, 12.94±0.2, 13.91±0.2, 14.13±0.2, 14.61±0.2, 16.04±0.2, 16.93±0.2, 17.76±0.2, 18.43±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.53±0.2, 21.87±0.2, 22.34 ±0.2, 22.62±0.2, 23.16±0.2, 23.55±0.2, 23.76±0.2, 24.18±0.2, 24.86±0.2, 25.39±0.2, 25.65±0.2, 26.04±0.2, 26.46±0.2, 26.96±0.2, 27.53±0.2, 28.03±0.2, 28.47±0.2, 29. or 02±0.2, 29.47±0.2, 29.70±0.2, 30.16±0.2, 30.98±0.2, 31.36±0.2, 31.87±0.2, 32.53±0.2, 33.38±0.2, 34.41±0.2, 35.63±0.2, 35.91±0.2, 36.59±0.2, 38.15±0.2, and 38.66±0.2; (d) crystalline Form D characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2θ angle values ​​independently selected from the group consisting of: 4.06±0.2, 8.03±0.2, 10.51±0.2, 10.84±0.2, 11.60±0.2, 12.06±0.2, 12.85±0.2, 14.04±0.2, 14.67±0.2, 16.08±0.2, 16.98±0.2, 17.36±0.2, 17.80±0.2, 18.36±0.2, 18.68±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2 , 20.46±0.2, 21.20±0.2, 21.66±0.2, 21.97±0.2, 22.38±0.2, 23.31±0.2, 23.80±0.2, 24.14±0.2, 24.31±0.2, 24.93±0.2, 25.52±0.2, 26.77±0.2, 27.28±0.2 , 27.48±0.2, 28.33±0.2, 28.75±0.2, 29.59±0.2, 30.10±0.2, 30.81±0.2, 31.20±0.2, 32.16±0.2, 32.61±0.2, 33.36±0.2, 36.05±0.2, 38.64±0.2 and 39.25±0.2.

[0036] Aspect 11. A crystalline form of an oxalate salt of Compound 2, which is (a) crystalline Form A, characterized by a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values ​​of 11.68±0.2, 15.36±0.2, and 21.61±0.2; preferably having 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 21.05±0.2, and 21.61±0.2; More preferably, the 2θ angle values ​​are 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2 and 23.48±0.2; Even more preferably having 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 18.39±0.2, 19.81±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 23.48±0.2, and 25.44±0.2; Even more preferably having 2θ angle values ​​of 7.69±0.2, 10.55±0.2, 11.68±0.2, 11.21±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 18.39±0.2, 19.81±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 22.49±0.2, 23.48±0.2, and 25.44±0.2; or (b) crystalline Form B characterized by a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values ​​of 11.80±0.2, 12.02±0.2, and 16.03±0.2; preferably having 2θ angle values ​​of 8.00±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, and 20.50±0.2; More preferably, the 2θ angle values ​​are 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, 20.50±0.2, 23.72±0.2 and 26.02±0.2; Even more preferably having 2θ angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, 16.83±0.2, 20.08±0.2, 20.50±0.2, 23.72±0.2, 24.09±0.2, and 26.02±0.2; Even more preferably having 2θ angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 13.92±0.2, 15.55±0.2, 16.03±0.2, 16.83±0.2, 20.08±0.2, 20.50±0.2, 23.72±0.2, 24.09±0.2, 26.02±0.2, and 28.21±0.2; or (c) crystalline Form C, characterized by a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values ​​of 10.42±0.2, 12.94±0.2, and 20.29±0.2; preferably having 2θ angle values ​​of 10.42±0.2, 12.94±0.2, 16.04±0.2, 18.91±0.2, 19.91±0.2, and 20.29±0.2; More preferably, the 2θ angle values ​​are 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2 and 24.18±0.2; Even more preferably having 2θ angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.87±0.2, 23.16±0.2, and 24.18±0.2; Even more preferably having 2θ angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.43±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.53±0.2, 21.87±0.2, 23.16±0.2, 24.18±0.2, and 28.47±0.2; or (d) crystalline Form D, characterized by a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values ​​of 10.51±0.2, 20.20±0.2, and 20.46±0.2; Preferably having 2θ angle values ​​of 10.51±0.2, 12.06±0.2, 12.85±0.2 and 16.08±0.2, 20.20±0.2, 20.46±0.2; More preferably, the 2θ angle values ​​are 10.51±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 20.20±0.2, 20.46±0.2, 21.66±0.2 and 23.80±0.2; Even more preferably having 2θ angle values ​​of 10.51 ± 0.2, 10.84 ± 0.2, 12.06 ± 0.2, 12.85 ± 0.2, 16.08 ± 0.2, 16.98 ± 0.2, 19.15 ± 0.2, 19.85 ± 0.2, 20.20 ± 0.2, 20.46 ± 0.2, 21.66 ± 0.2, and 23.80 ± 0.2; Even more preferably have 2θ angle values ​​of 10.51±0.2, 10.84±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 18.36±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2, 20.46±0.2, 21.20±0.2, 21.66±0.2, 22.38±0.2, and 23.80±0.2.

[0037] Aspect 12. A crystalline form of the oxalate salt of Compound 2, characterized in that it is selected from Figure 1A , Figure 2A , Figure 3A and Figure 4A The powder X-ray diffraction patterns of the composition groups shown in the figures are substantially identical.

[0038] Aspect 13. A method for preparing a crystalline form of an oxalate salt of Compound 2, the method comprising: Step (1) dissolving the oxalate described in aspect 4 in EtOH, and slowly evaporating the resulting solution to obtain the crystalline form; or Step (2) dissolving the oxalate described in aspect 4 in DCM, and slowly evaporating the resulting solution to obtain the crystalline form; or Step (3) suspending the oxalate described in aspect 4 in CPME, and stirring the resulting mixture to obtain the crystalline form; or Step (4) suspending the oxalate described in aspect 4 in toluene and stirring the mixture to obtain the crystalline form, Preferably, the oxalate salt as described in aspect 4 is in an amorphous form.

[0039] Aspect 14. A method for preparing a crystalline form according to aspect 13, wherein the time of step (1) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, and even more preferably 1, 2, 3, 4 or 5 days; The duration of step (2) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, even more preferably 1, 2, 3, 4 or 5 days; The duration of step (3) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, and even more preferably 1, 2, 3, 4, 5, 6 or 7 days; The duration of step (4) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, and even more preferably 1, 2, 3, 4, 5, 6 or 7 days.

[0040] Aspect 15. A method for preparing a crystalline form according to aspects 13-14, wherein the oxalate / EtOH (mg / ml) in step (1) is 1:1 to 100:1, preferably 1:1 to 50:1, more preferably 20:1 to 40:1, even more preferably 30:1; The oxalate / DCM (mg / ml) in step (2) is 1:1 to 100:1, preferably 1:1 to 50:1, more preferably 20:1 to 40:1, even more preferably 30:1; The oxalate / CPME (mg / ml) in step (3) is 1:1 to 100:1, preferably 20:1 to 80:1, more preferably 40:1 to 70:1, even more preferably 60:1; The oxalate / toluene (mg / ml) in step (4) is 1:1 to 100:1, preferably 20:1 to 80:1, more preferably 40:1 to 70:1, even more preferably 60:1.

[0041] Aspect 16. A method for preparing a crystalline form of the oxalate salt of Compound 2, wherein the temperature of step (1) is 0°C to 50°C, preferably 10°C to 40°C, more preferably 20°C to 30°C, even more preferably 20°C to 25°C or room temperature; The temperature of step (2) is 0°C to 50°C, preferably 10°C to 40°C, more preferably 20°C to 30°C, even more preferably 20°C to 25°C or room temperature; The temperature of step (3) is 0°C to 50°C, preferably 10°C to 40°C, more preferably 20°C to 30°C, even more preferably 20°C to 25°C or room temperature; The temperature of step (4) is 10°C to 110°C, preferably 30°C to 100°C, more preferably 60°C to 90°C, even more preferably 80°C or room temperature.

[0042] Aspect 17. The method for preparing the crystalline form as described in aspects 13-16, wherein the starting material is selected from amorphous, type A, type B, type C, and type D; preferably amorphous.

[0043] Aspect 18. A method for preparing a crystalline form according to aspects 13-17, wherein the method further comprises: Step (5): dissolving the free base of compound 3 in a solvent, and then adding oxalic acid to obtain an oxalate, wherein compound 3 is Preferably, the solvent in step (5) is methyl tert-butyl ether; More preferably, oxalic acid is added using a methyl tert-butyl ether solution; Even more preferably, step (5) is performed at room temperature or at 20°C-30°C.

[0044] Aspect 19. The crystalline form according to any one of aspects 5 to 12 or the salt according to any one of aspects 1 to 4 is used as an intermediate for the preparation of Sonrotoclax.

[0045] Aspect 20. Provided herein is a method for preparing Sonrotoclax, or a salt thereof, which comprises reacting a salt having the formula (I) with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

[0046] In one embodiment of aspect 20, the reaction occurs in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP).

[0047] Aspect 21. Provided herein is a method for preparing Sonrotoclax, or a salt thereof, the method comprising reacting a salt having formula (I) with an acid or a base to provide (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, or a salt thereof.

[0048] In one embodiment of aspect 21, the acid is HCl, or the base is NaOH.

[0049] Aspect 22. Provided herein is a method for producing Sonrotoclax, the method comprising reacting (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, or a salt thereof and 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

[0050] In one embodiment of Aspect 22, the reaction occurs in the presence of EDCI and DMAP.

[0051] In one embodiment of aspect 23, provided herein is a method for preparing a pharmaceutical composition comprising Sonrotoclax, the method comprising mixing Sonrotoclax with a pharmaceutically acceptable excipient, wherein Sonrotoclax is prepared according to the method provided herein.

[0052] Numbered Examples: Example 1. A salt having formula (I): wherein [acid] is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentisic acid, nicotinic acid, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; n is from about 0.5 to about 3. Embodiment 2. The salt of Embodiment 1, wherein [acid] is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and / or nitric acid. Embodiment 3. The salt as described in Embodiment 1, wherein [acid] is selected from tartaric acid (L-tartaric acid or D-tartaric acid), malic acid, citric acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; preferably, [acid] is selected from oxalic acid. Embodiment 4. The salt as described in Embodiment 1, which is an oxalate salt having formula (II): wherein n is from about 0.5 to about 3; Preferably, n is 0.5 to 2; more preferably, n is 0.5 to 1.5; even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0; even more preferably, n is 1.0 Even more preferably, the salt is an oxalate salt having formula (III): Example 5. A crystalline form of a salt of formula IV wherein [acid] is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentisic acid, nicotinic acid, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; [Solvent] is selected from H2O or an organic solvent; n is a number from about 0.5 to about 3; m is a number from about 0.0 to about 5.0. Embodiment 6. The crystalline form of Embodiment 5, wherein [acid] is selected from the group consisting of an inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and / or nitric acid; or an organic acid selected from fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentisic acid, nicotinic acid, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; Preferably, [acid] is selected from tartaric acid (L-tartaric acid or D-tartaric acid), malic acid, citric acid, p-toluenesulfonic acid, D-DTTA, maleic acid and / or oxalic acid; More preferably, [the acid] is selected from oxalic acid. Embodiment 7. The crystalline form of any one of Embodiments 5-6, wherein n is from about 0.5 to about 3; Preferably, n is from 0.5 to 2; more preferably, n is from 0.5 to 1.5; even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0; even more preferably, n is 1.0. Embodiment 8. A crystalline form as described in any of Embodiments 5-7, wherein the [solvent] is selected from MeOH, EtOH, i-PrOH, n-PrOH, n-BuOH, t-BuOH, DCM, CPME, toluene, acetone, butanone, pentanone, H2O, MeCN, THF, diethyl ether, propyl ether, n-heptane, hexane, 1,4-dioxane or EtOAc. Embodiment 9. A crystalline form as described in any one of embodiments 5-8, wherein m is a number from about 0.0 to about 3.0, preferably from about 0.0 to about 2.0, more preferably, m is a number selected from the group consisting of: 0.1±0.1, 0.5±0.1, 1.0±0.2, 1.5±0.2 and 2.0±0.2, even more preferably, m is 0 to 0.2, 0.95 to 1.05, 1.05 more preferably, m is 0.98 to 1.02, 1.08 to 1.12 or 1.48 to 1.52, 1.95 to 2.15; even more preferably, m is 0, 0.1, 0.2, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 or 7.0. Embodiment 10. A crystalline form as described in any one of embodiments 5-9, which is (a) Oxalate crystalline Form A, characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2θ angle values ​​independently selected from the group consisting of: 3.89±0.2, 7.69±0.2, 10.55±0.2, 10.84±0.2, 11.21±0.2, 11.68±0.2, 12.31±0.2, 13.02±0.2, 13.83±0.2, 14.69±0.2, 15.36±0.2, 15.58±0.2, 16.60±0.2, 17.58±0.2, 18.39±0.2, 18.98±0.2, 19.32±0.2, 19.81±0.2, 20.37±0.2 2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 22.49±0.2, 23.09±0.2, 23.48±0.2, 24.15±0.2, 24.76±0.2, 25.44±0.2, 25.66±0.2, 26.18±0.2, 26.67±0.2, 27.00±0.2, 28.1 1±0.2, 28.71±0.2, 29.09±0.2, 29.55±0.2, 29.91±0.2, 31.52±0.2, 32.18±0.2, 32.80±0.2, 34.49±0.2, 34.97±0.2, 36.66±0.2, 38.52±0.2, 39.32±0.2, and 39.71±0.2; or (b) oxalate crystalline Form B, characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2θ angle values ​​independently selected from the group consisting of: 4.05±0.2, 8.00±0.2, 10.79±0.2, 11.23±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 12.95±0.2, 13.92±0.2, 15.55±0.2, 16.03±0.2, 16.83±0.2, 17.14±0.2, 17.76±0.2, 18.41±0.2, 19.38±0.2, 20.08±0.2 2, 20.50±0.2, 21.04±0.2, 21.66±0.2, 22.08±0.2, 22.52±0.2, 23.34±0.2, 23.72±0.2, 24.09±0.2, 24.82±0.2, 25.31±0.2, 25.66±0.2, 26.02±0.2, 27.21 ±0.2, 27.78±0.2, 28.21±0.2, 28.53±0.2, 29.01±0.2, 31.06±0.2, 31.45±0.2, 32.28±0.2, 33.02±0.2, 34.67±0.2, 35.30±0.2, 36.02±0.2, and 38.00±0.2; or (c) Oxalate crystalline Form C, characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2θ angle values ​​independently selected from the group consisting of: 3.80±0.2, 4.01±0.2, 8.00±0.2, 10.42±0.2, 11.31±0.2, 11.55±0.2, 12.02 ±0.2, 12.94±0.2, 13.91±0.2, 14.13±0.2, 14.61±0.2, 16.04±0.2, 16.93±0.2, 17.76±0.2, 18.43±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.53±0.2, 21.87±0.2, 22.3 4±0.2, 22.62±0.2, 23.16±0.2, 23.55±0.2, 23.76±0.2, 24.18±0.2, 24.86±0.2, 25.39±0.2, 25.65±0.2, 26.04±0.2, 26.46±0.2, 26.96±0.2, 27.53±0.2, 28.03±0.2, 28.47±0.2, 29. or 02±0.2, 29.47±0.2, 29.70±0.2, 30.16±0.2, 30.98±0.2, 31.36±0.2, 31.87±0.2, 32.53±0.2, 33.38±0.2, 34.41±0.2, 35.63±0.2, 35.91±0.2, 36.59±0.2, 38.15±0.2, and 38.66±0.2; (d) the oxalate crystalline Form D is characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2θ angle values ​​independently selected from the group consisting of: 4.06±0.2, 8.03±0.2, 10.51±0.2, 10.84±0.2, 11.60±0.2, 12.06±0.2, 12.85±0.2, 14.04±0.2, 14.67±0.2, 16.08±0.2, 16.98±0.2, 17.36±0.2, 17.80±0.2, 18.36±0.2, 18.68±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2 .2, 20.46±0.2, 21.20±0.2, 21.66±0.2, 21.97±0.2, 22.38±0.2, 23.31±0.2, 23.80±0.2, 24.14±0.2, 24.31±0.2, 24.93±0.2, 25.52±0.2, 26.77±0.2, 27.28±0. 2, 27.48±0.2, 28.33±0.2, 28.75±0.2, 29.59±0.2, 30.10±0.2, 30.81±0.2, 31.20±0.2, 32.16±0.2, 32.61±0.2, 33.36±0.2, 36.05±0.2, 38.64±0.2 and 39.25±0.2. Embodiment 11. A crystalline form as described in any one of embodiments 5-10, which is (a) oxalate crystalline Form A, characterized by a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values ​​of 11.68±0.2, 15.36±0.2, and 21.61±0.2; preferably having 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 21.05±0.2, and 21.61±0.2; More preferably, the 2θ angle values ​​are 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2 and 23.48±0.2; Even more preferably having 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 18.39±0.2, 19.81±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 23.48±0.2, and 25.44±0.2; Even more preferably having 2θ angle values ​​of 7.69±0.2, 10.55±0.2, 11.68±0.2, 11.21±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 18.39±0.2, 19.81±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 22.49±0.2, 23.48±0.2, and 25.44±0.2; or (b) oxalate crystalline Form B, characterized by a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values ​​of 11.80±0.2, 12.02±0.2, and 16.03±0.2; preferably having 2θ angle values ​​of 8.00±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, and 20.50±0.2; More preferably, the 2θ angle values ​​are 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, 20.50±0.2, 23.72±0.2 and 26.02±0.2; Even more preferably having 2θ angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, 16.83±0.2, 20.08±0.2, 20.50±0.2, 23.72±0.2, 24.09±0.2, and 26.02±0.2; Even more preferably having 2θ angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 13.92±0.2, 15.55±0.2, 16.03±0.2, 16.83±0.2, 20.08±0.2, 20.50±0.2, 23.72±0.2, 24.09±0.2, 26.02±0.2, and 28.21±0.2; or (c) oxalate crystalline Form C, characterized by a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values ​​of 10.42±0.2, 12.94±0.2, and 20.29±0.2; preferably having 2θ angle values ​​of 10.42±0.2, 12.94±0.2, 16.04±0.2, 18.91±0.2, 19.91±0.2, and 20.29±0.2; More preferably, the 2θ angle values ​​are 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2 and 24.18±0.2; Even more preferably having 2θ angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.87±0.2, 23.16±0.2, and 24.18±0.2; Even more preferably having 2θ angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.43±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.53±0.2, 21.87±0.2, 23.16±0.2, 24.18±0.2, and 28.47±0.2; or (d) oxalate crystalline Form D, characterized by a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values ​​of 10.51±0.2, 20.20±0.2, and 20.46±0.2; Preferably having 2θ angle values ​​of 10.51±0.2, 12.06±0.2, 12.85±0.2 and 16.08±0.2, 20.20±0.2, 20.46±0.2; More preferably, the 2θ angle values ​​are 10.51±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 20.20±0.2, 20.46±0.2, 21.66±0.2 and 23.80±0.2; Even more preferably having 2θ angle values ​​of 10.51 ± 0.2, 10.84 ± 0.2, 12.06 ± 0.2, 12.85 ± 0.2, 16.08 ± 0.2, 16.98 ± 0.2, 19.15 ± 0.2, 19.85 ± 0.2, 20.20 ± 0.2, 20.46 ± 0.2, 21.66 ± 0.2, and 23.80 ± 0.2; Even more preferably have 2θ angle values ​​of 10.51±0.2, 10.84±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 18.36±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2, 20.46±0.2, 21.20±0.2, 21.66±0.2, 22.38±0.2, and 23.80±0.2. Embodiment 12. The crystalline form of any one of Embodiments 5-11, characterized essentially by a powder X-ray diffraction pattern selected from the group consisting of: Figure 1A , Figure 2A , Figure 3A and Figure 4A . Embodiment 13. A method for preparing a crystalline form as described in any one of embodiments 5-12, the method comprising: Step (1) dissolving the oxalate described in Example 4 in EtOH and slowly evaporating the resulting solution to obtain the crystalline form; or Step (2) dissolving the oxalate salt as described in Example 4 in DCM and slowly evaporating the resulting solution to obtain the crystalline form; or Step (3) suspending the oxalate salt as described in Example 4 in CPME and stirring the resulting mixture to obtain the crystalline form; or Step (4) The oxalate salt as described in Example 4 is suspended in toluene and the resulting mixture is stirred to obtain the crystalline form. Embodiment 14. A method for preparing the crystalline form as described in Embodiment 13, wherein the time of step (1) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, even more preferably 1, 2, 3, 4 or 5 days; The duration of step (2) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, even more preferably 1, 2, 3, 4 or 5 days; The duration of step (3) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, and even more preferably 1, 2, 3, 4, 5, 6 or 7 days; The duration of step (4) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, and even more preferably 1, 2, 3, 4, 5, 6 or 7 days. Embodiment 15. The method for preparing the crystalline form as described in Embodiments 13-14, wherein the oxalate / EtOH (mg / ml) in step (1) is 1:1 to 100:1, preferably 1:1 to 50:1, more preferably 20:1 to 40:1, even more preferably 30:1; The oxalate / DCM (mg / ml) in step (2) is 1:1 to 100:1, preferably 1:1 to 50:1, more preferably 20:1 to 40:1, even more preferably 30:1; The oxalate / CPME (mg / ml) in step (3) is 1:1 to 100:1, preferably 20:1 to 80:1, more preferably 40:1 to 70:1, even more preferably 60:1; The oxalate / toluene (mg / ml) in step (4) is 1:1 to 100:1, preferably 20:1 to 80:1, more preferably 40:1 to 70:1, even more preferably 60:1. Embodiment 16. A method for preparing the crystalline form as described in Embodiments 13-15, wherein the temperature of step (1) is 0°C to 50°C, preferably 10°C to 40°C, more preferably 20°C to 30°C, even more preferably 20°C to 25°C or room temperature; The temperature of step (2) is 0°C to 50°C, preferably 10°C to 40°C, more preferably 20°C to 30°C, even more preferably 20°C to 25°C or room temperature; The temperature of step (3) is 0°C to 50°C, preferably 10°C to 40°C, more preferably 20°C to 30°C, even more preferably 20°C to 25°C or room temperature; The temperature of step (4) is 10°C to 110°C, preferably 30°C to 100°C, more preferably 60°C to 90°C, even more preferably 80°C or room temperature. Embodiment 17. The method for preparing the crystalline form as described in Embodiments 13-16, wherein the starting material is selected from amorphous, type A, type B, type C, type D; preferably amorphous. Embodiment 18. A method for preparing the crystalline form as described in Embodiments 13-17, wherein the method further comprises: Step (5): dissolving the free base of compound 3 in a solvent, and then adding oxalic acid to obtain an oxalate, wherein compound 3 is Preferably, the solvent in step (5) is methyl tert-butyl ether; More preferably, oxalic acid is added using a methyl tert-butyl ether solution; Even more preferably, the temperature of step (5) is room temperature or 20°C-30°C. Embodiment 19. A method of a crystalline form as described in any of embodiments 5-12 or a salt as described in any of embodiments 1-4, wherein the crystalline form or the salt is used as an intermediate in the preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide. Examples abbreviation

[0053] Instruments and parameters

[0054] For XRPD analysis, unless otherwise specified, PANalytical Empyrean and X'Pert3 X-ray powder diffractometers were used to characterize the physical forms obtained in the present disclosure. The XRPD parameters used are listed below.

[0055] For XRPD analysis, a Bruker D8 advanced X-ray powder diffractometer or equivalent was also used to characterize Form A and Form U. The XRPD parameters used are listed below.

[0056] Unless otherwise specified, TGA and DSC were used to characterize the physical forms obtained in the present disclosure, wherein TGA data were collected using a TA Q500 / Q5000 TGA from TA Instruments; and DSC was performed using a TA Q200 / Q2000 DSC from TA Instruments. The detailed parameters used are listed below. parameter TGA DSC mDSC method Slope Slope modulation Sample tray Aluminum, open Aluminum, crimp Aluminum, crimp temperature RT - desired temperature 25℃-Required temperature 16℃-Required temperature Heating rate 10℃ / min 10℃ / min 3℃ / min Purge gas N2 N2 N2

[0057] For TGA and DGA analysis of Form A or U, some instruments were also used to perform the test, wherein TGA data were collected using a NETZSCHTG 209F1 instrument; and DSC was performed using a TA Q 20 or TA DSC 250 instrument. The detailed parameters used are listed below. parameter TGA DSC method Slope Slope Sample tray Aluminum, open Aluminum, sealed temperature RT - desired temperature RT - desired temperature Heating rate 10℃ / min 10℃ / min Purge gas N2 N2

[0058] The DVS obtained in the present disclosure was measured by SMS (Surface Measurement Systems) DVS Intrinsic, without special instructions (Method A). The relative humidity at 25°C was calibrated according to the deliquescent points of LiCl, Mg(NO3)2 and KCl. The parameters of the DVS test are listed below.

[0059] The DVS of Forms A and U was also measured using SMS (Surface Measurement Systems) DVS Intrinsic (Method B). The relative humidity at 25°C was calibrated based on the deliquescent points of LiCl, Mg(NO3)2 and KCl. The parameters of the DVS test are listed below. parameter DVS temperature 25℃ Gas and flow rate N2, 200mL / min dm / dt <0.01min Minimum dm / dt stability duration 60min Maximum balancing time 180min RH Range Cycle: 40%-0%-95%-0%-40%RH

[0060] Using Rigaku XtaLAB Synergy R (CuK radiation, ) diffractometer to collect single crystal X-ray diffraction data at 120 K. The instrument parameters are listed below.

[0061] The following examples are intended to further illustrate certain embodiments of the present disclosure and are not intended to limit the scope of the present disclosure.

[0062] Seven acids and seven organic solvents were used for the salt formation of compound 2, see Table 1.

[0063] In one example, a solution of compound 2 (1.0 g, 1.73 mmol) in MTBE (10 mL) and oxalic acid (0.16 g, 1.73 mmol) were added dropwise. The reaction mixture was stirred for about 6 hours and filtered to obtain a wet cake of 4-(2-{(2S)-2-[2-(propane-2-yl)phenyl]pyrrolidin-1-yl}-7-azaspiro[3.5]nonane-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoic acid methyl ester oxalate (compound 3). Solids have low hygroscopic properties, and solids have poor electrostatic ability, so they are not easily adsorbed on objects.

[0064] Other salts of compound 2 were prepared by using other acids in a similar manner to that disclosed for compound 3. The amounts of other acids used were as follows: D-(-)-tartaric acid (0.26 g, 1.73 mmol), p-toluenesulfonic acid (0.3 g, 1.73 mmol), D-DTTA (0.67 g, 1.73 mmol), citric acid (0.33 g, 1.73 mmol), malic acid (0.23 g, 1.73 mmol), maleic acid (0.20 g, 1.73 mmol); and other organic solvents were used in a volume of 10 mL.

[0065] The corresponding physical forms of the salt of compound 2 are listed in Table 1. The results show that when the acid used for salt formation is oxalic acid or D-DTTA, the obtained salt is in solid form in certain organic solvents. Considering the simplified method, D-DTTA / MTBE and oxalic acid / MTBE are preferred as salt-forming systems, while D-DTTA (MW 386.35 g / mol) may cause more waste to the reaction than oxalic acid (MW 90.03 g / mol).

[0066] Table 1

[0067] Synthesis of Compound-3

[0068] The free base of 3 (21 g) was dissolved in methyl tert-butyl ether (110 g). The temperature was adjusted to 20°C-30°C, and then a solution of oxalic acid (3.33 g) in methyl tert-butyl ether (110 g) was added over 2 h. The solution was stirred at 20°C-30°C for 16 h. The resulting solid was filtered and washed with methyl tert-butyl ether (20 g). The filtered solid was dried at a temperature below 45°C for 20-28 h to become amorphous.

[0069] Example 1A: Preparation of Compound 3 Form A (Form A)

[0070] A sample of crystalline Form A of Compound 3 was obtained by slow evaporation of a solution of amorphous form of Compound 3 in EtOH at room temperature.

[0071] Procedure: Weigh 30 mg of amorphous solid of compound 3 into a 3 mL glass vial and add 1 mL of EtOH to the vial to obtain a clear solution. The solution was evaporated at room temperature for 3 days to induce precipitation to obtain crystalline Form A.

[0072] The X-ray powder diffraction (XRPD) pattern (performed on a Bruker D8 advanced X-ray powder diffractometer) was used to characterize the obtained Form A, which showed that Form A was a crystalline form, see Figure 1AThe characteristic peaks and peak intensity percentages obtained from the XRPD analysis are listed in Table 1A.

[0073] Table 1A. XRPD pattern of Compound 3 Form A

[0074] The TGA results showed that the weight loss from 100°C to 150°C was 2.7%, and the weight loss from 160°C to 250°C was 14%. The DSC results showed that the three endothermic peaks were located at 51°C, 114°C and 192°C (onset temperature) ( Figure 1B ).exist 1 In the HNMR spectrum, about 0.27% of EtOH ( Figure 1C ).

[0075] Example 2A: Preparation of Compound 3 Form B (Form B)

[0076] A sample of crystalline Form B of Compound 3 was obtained by slow evaporation of a solution of amorphous form of Compound 3 in DCM at room temperature.

[0077] Procedure: Weigh 30 mg of amorphous solid of compound 3 into a 3 mL glass vial and add 1 mL of DCM to the vial to get a clear solution. The solution was evaporated at room temperature to induce precipitation to obtain crystalline Form B.

[0078] The XRPD pattern used to characterize the obtained Form B showed that Form B was a crystalline form, see Figure 2A The characteristic peaks and peak intensity percentages obtained from the XRPD analysis are listed in Table 2A.

[0079] Table 2A. XRPD pattern of Compound 3 Form B

[0080] The TGA results showed that the weight loss from 100°C to 150°C was 0.9%, and the weight loss from 170°C to 250°C was 8.6%. The DSC results showed that the three endothermic peaks were located at 53°C, 124°C and 192°C (onset temperature) ( Figure 2B ).exist 1 In the H NMR spectrum, about 3% DCM ( Figure 2C ).

[0081] Example 3A: Preparation of Compound 3 Form C (Form C)

[0082] A sample of crystalline Form C of Compound 3 was obtained by slurrying an amorphous form of Compound 3 in CPME at room temperature.

[0083] Procedure: Weigh 30 mg of amorphous solid of compound 3 into a 3 mL glass vial, and add 0.5 mL of CPME to the vial to obtain a suspension. The mixture was magnetically stirred at 800 RPM at room temperature for 4 days to obtain crystalline Form C.

[0084] The XRPD pattern used to characterize the obtained Form C showed that Form C was a crystalline form, see Figure 3A The characteristic peaks and peak intensity percentages obtained from the XRPD analysis are listed in Table 3A.

[0085] Table 3A. XRPD Pattern of Compound 3 Form C

[0086] The TGA results showed that the weight loss from 95°C to 150°C was 4.1%, and the weight loss from 150°C to 250°C was 14.8%. The DSC results showed two endothermic peaks located at 131°C and 194°C (onset temperature) ( Figure 3B ).exist 1 In the H NMR spectrum, about 5.9% CPME ( Figure 3C ).

[0087] Example 4A: Preparation of Compound 3 Form D (Form D)

[0088] A sample of crystalline Form D of Compound 3 was obtained by slurrying an amorphous form of Compound 3 in toluene at 80°C.

[0089] Procedure: Weigh 30 mg of amorphous solid of compound 3 into a 3 mL glass vial, and add 0.5 mL of toluene to the vial to obtain a suspension. The mixture was magnetically stirred at 800 RPM at 80° C. for 4 days to obtain crystalline Form D.

[0090] The XRPD pattern used to characterize the obtained Form D showed that Form D was a crystalline form, see Figure 4A The characteristic peaks and peak intensity percentages obtained from the XRPD analysis are listed in Table 4A.

[0091] Table 4A. XRPD pattern of Compound 3 Form D

[0092] The TGA results showed that the weight loss from 120°C to 170°C was 3.1%, and the weight loss from 170°C to 250°C was 13.5%. The DSC results showed two endothermic peaks located at 132°C and 194°C (onset temperature) ( Figure 4B ).exist 1 In the H NMR spectrum, about 5.2% toluene ( Figure 4C ).

[0093] Example 5: Sonrotoclax

[0094] Step 1: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0095] (S)-methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate was synthesized according to the method in WO 2019210828 (e.g., Example F43), which is incorporated by reference in its entirety.

[0096] To a solution of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonane-7-yl)benzoic acid methyl ester (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aqueous NaOH (3.5 M). It was stirred at room temperature overnight. After THF and MeOH were removed in vacuo, 3.5 L of water was added to the residue. The resulting mixture was adjusted to pH=5-6 with 3N HCl under stirring at room temperature. The precipitate was filtered and dried in vacuo to give the product as a white solid (102.4 g, yield: 99%). 1 HNMR(400MHz,DMSO-d6)δppm:12.13(s,1H),11.58(s,1H),7.95(s,1H),7.67(d,J =8.0Hz,1H),7.56-7.40(m,2H),7.35(s,1H),7.27-7.04(m,3H),6.68(d,J=8.0Hz, 1H),6.32(s,2H),3.62(s,1H),3.32-3.26(m,1H),3.10-3.04(m,4H),2.35-2.30( m,1H),2.9-2.15(m,1H),1.74-1.64(m,4H),1.52-1.37(m,6H),1.28-1.06(m,6H). MS(ESI,m / e)[M+1] + 564.9.

[0097] Step 2: Sonrotoclax A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (44 g, 78 mmol), 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (26.8 g, 78 mmol), TEA (15.7 g, 156 mmol), EDCI (19.4 g, 101 mmol) and DMAP (19 g, 156 mmol) in anhydrous DCM (880 mL) was stirred overnight at room temperature. The reaction was monitored by HPLC. After the starting material (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid was completely consumed, the reaction mixture was heated to about 35°C and N 1 ,N 1 -dimethylethane-1,2-diamine (17.2 g, 195 mmol). The reaction was stirred for another 12 hours. The mixture was washed twice with 10 wt% AcOH aqueous solution (300 mL × 2), and then washed with saturated NaHCO3 aqueous solution (300 mL × 2). The organic layer was collected and concentrated to about 90 mL. 22 g of silica gel was added and stirred for 2 hours. After filtering, 180 mL of EA was added to the filtrate under reflux and further stirred for 5 hours. After the mixture was cooled to room temperature, the precipitate was filtered, and the wet cake was then washed twice with EA (180 mL). Sonrotoclax (48 g, yield: 69.5%) was obtained after drying in vacuum at 80°C-90°C. 1H NMR(DMSO-d6)δppm:11.65(s,1H),11.11(br,1H),8.58-8.39(m,2H),8.00(d,J=2.8Hz,1H),7.74(d,J=8.8Hz,1H),7.57-7.37(m,4H),7.30-7.10(m,3H),7.00(d,J=9.2Hz,1H),6.65(d,J=1.2Hz,1H),6.35(s,1H),6.17(s,1H),4.24(s,1H),3.39-3.20(m,5H),3.04-2.88(m,4H),2.23(s,1H),1.94-1.47(m,11H),1.44-1.26(m,7H),1.19(d,J=8.0Hz,3H),1.14(d,J=8.0Hz,3H),1.10(s,4H)。MS(ESI,m / e)[M+1] + 889.9。

Claims

1. A crystalline form of compound 3, Its basic characteristics are A powder X-ray diffraction pattern substantially consistent with the powder X-ray diffraction pattern shown in a figure selected from the group consisting of FIG. 1A , FIG. 2A , FIG. 3A , and FIG. 4A .

2. The crystalline form of claim 1, wherein The powder X-ray diffraction pattern is substantially consistent with the powder X-ray diffraction pattern shown in FIG. 1A .

3. The crystalline form of claim 1, wherein The powder X-ray diffraction pattern is substantially consistent with the powder X-ray diffraction pattern shown in FIG. 2A .

4. The crystalline form of claim 1, wherein The powder X-ray diffraction pattern is substantially consistent with the powder X-ray diffraction pattern shown in FIG. 3A .

5. The crystalline form of claim 1, wherein The powder X-ray diffraction pattern is substantially consistent with the powder X-ray diffraction pattern shown in FIG. 4A .

6. A method for preparing Sonrotoclax or a salt thereof, the method comprising making a salt having formula (I) with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide, wherein [acid] is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid, lauric acid, stearic acid, gentisic acid, nicotinic acid, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, (+)-di-1,4-toluoyl-D-tartaric acid (D-DTTA), maleic acid and / or oxalic acid; and n is from about 0.5 to about 3.

7. A method as claimed in claim 6, which comprises reacting a salt having formula (I) with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP).

8. The method of claim 6, wherein: The salt of formula (I) is in crystalline form as claimed in claim 1.

9. A method for preparing Sonrotoclax or a salt thereof, the method comprising reacting the crystalline form of claim 1 with an acid or a base to provide (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, or a salt thereof.

10. The method of claim 9, wherein: The acid is HCl, or the base is NaOH.

11. The method of claim 9, further comprising reacting (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, or a salt thereof and 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

12. The method of claim 11, comprising reacting (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide in the presence of EDCI and DMAP.

13. A method for preparing a pharmaceutical composition comprising Sonrotoclax, the method comprising mixing Sonrotoclax with a pharmaceutically acceptable excipient, wherein Sonrotoclax is prepared by the method of any one of claims 6 to 12.

14. A pharmaceutical composition comprising Sonrotoclax or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein Sonrotoclax is prepared by the method of any one of claims 6 to 11.

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